1. Field of the Invention
This invention relates to a novel azetidinone compound of the following general formula (I), which is useful as an intermediate of β-methylcarbapenem antibiotics and its preparing process: wherein, R is a hydrogen atom or a protecting group of hydroxy; R1 and R2 are independently C1-C15 alkyl, benzyl or cyclized to be 5 or 6-membered ring which is cyclic hydrocarbon or heterocyclic compound containing at least one of O and S; R3 is a lower alkyl or a lower alkyl ester; R4 is benzene or benzene substituted with halogen atom, a lower alkoxy or nitro; and, the methyl group in 1′ position is R configuration, which is expressed by β-methyl in all general formula hereunder.
Further, this invention relates to a process for preparing a novel azetidinone compound of the general formula (I) by reacting 4-acetoxy-azetidinone compound of the general formula (II) with α-halopropionamide compound of the general formula (III): wherein R, R1, R2, R3 and R4 are the same as defined above; and, X is a halogen atom.
Further, this invention relates to α-halopropionamide compound of the general formula (III), a novel stereoselective additive.
The general formula (I) compound with better stereoselectivity may be made available using the general formula (III) compound.
Further, this invention relates to α-halopropionamide compound of the novel general formula (III) by reacting monocyclic compound of the general formula (VIII) with 2-halopropionic acid of the general formula (IX) or its activated complex. wherein R1, R2, R3, R4, and X are the same as defined above.
Further, this invention relates to a novel process for preparing β-methylcarbapenem ester compound of the general formula (V).
More specifically, the general formula (V) compound may be made available in a manner such that N-substituted azetidinone compound of the general formula (XI), so obtained by reacting the general formula (I) compound with haloacetate compound of the general formula (X), is further under cyclization and esterification in situ. wherein R, R1, R2, R3, R4, and X are the same as defined above. R5, which is a protecting group of carboxyl to be easily removed by the common process, includes a lower alkyl, a lower alkenyl, a halogeno-lower alkyl, nitrobenzyl, a lower alkoxy-benzyl or benzhydryl; OA, which is an esterified hydroxy group which can be easily substituted by —S—R6 (R6 is the corresponding heterocyclic compound exhibiting antibiotic activity), includes —OP(O)(OR7)2 (R7 is aryl or a lower alkyl), a substituted or unsubstituted lower alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, trifluoromethanesulfonyl), aryloxycarbonyl (e.g., benzyloxycarbonyl) and among them, it is preferred to employ some esterified hydroxyl groups selected from diarylphosphoryloxy, di-lower alkyl phosphoryloxy, a substituted or unsubstituted lower alkylsulfonyl, substituted or unsubstituted arylsulfonyl.
Further, this invention relates to a novel process for preparing 1′β-methylazetidinone compound of the general formula (IV).More specifically, the general formula (IV) compound may be made available via hydrolysis of the general formula (I) compound. wherein R is the same as defined above.
2. Description of the Related Art
β-methylcarbapenem antibiotic of the following general formula (XII) has a wide spectrum of antibiotic activity against Gram-negative bacteria including Pseudomonas aeruginosa and Gram-positive bacteria as well as penicillin- or cephalosporin-resistant bacteria.
The typical examples of β-methylcarbapenem antibiotic include meropenem (Europe Publication Patent No. 126587) and biapenem (Japan Publication Patent Pyung 1-25779), and a number of other β-methylcarbapenem antibiotic has been under development.
The currently known synthesis process for the preparation of β-methylcarbapenem antibiotic are made available through the following two processes. wherein R and R5 are the same as defined above; and R6 is a heterocyclic compound exhibiting an antibiotic activity.
The first process comprises the steps of:
(1) generating β-methylazetidinone compound of the general formula (IV) is prepared using 4-acetoxy-azetidinone compound of the general formula (II) as starting material in the presence of diverse stereoselective additives; and,
(2) preparing the general formula (V) compound, a final intermediate of carbapenem antibiotic, from the general formula (IV) compound via 5 or 6 steps, followed by preparing β-methylcarbapenem antibiotic of the general formula (XII). Now that the process for preparing the general formula (V) compound, a final intermediate of carbapenem antibiotic from the general formula (IV) compound has been well disclosed in Japan Publication Patent Sho 63-188662, this invention does not discussed such process in detail.
The introduction of 1′β-methyl group in the aforementioned reactions in Aldol-type has been known with better stereoselectivity, but a variety of reagents used for these reactions, including tin triplate, titanium chloride or dibutylboron triplate, are uneasy to be handled and expensive, thus making it difficult to ensure the large-scale production of β-methylcarbapenem antibiotics.
Some similar process has been disclosed in a number of literatures (Japan Publication Patent No. 87-252786): J.A.C.S. vol. 108, pp. 4675-4676, 1986: same journal vol. 108, pp. 4673-4675, 1986: J. Antibiotics, pp. 374, 1989, Tetrahedron, pp. 9657, 1995: Terahedron Letters, vol. 27, pp. 5687, 1986).
Such process, which is designed to synthesize the general formula (V) compound, a final intermediate of carbapenem antibiotic from the general formula (IV) compound via 5 or 6 steps, proven to have better yield in each process step but requires a longer time in the whole preparing process.
The second process developed by Tanabe Co. of Japan is designed to improve some shortcomings encountered with the first process.
More specifically, the second process comprises the steps of:
(1) generating 1′β-methyl intermediate of the following general formula (VII) in Reformatsky reaction using 4-acetoxy-azetidinone compound of the general formula (II) as starting material in the presence of stereoselective additive of the general formula (VI) to easily handle zinc or magnesium; and,
(2) hydrolyzing the general formula (VII) compound to obtain either general formula (IV) compound of the first process, or to generate the general formula (V) compound from the general formula (VII) compound via N-alkylation, cyclization and esterification (Korea Patent Registration No. 10-231223), followed by preparing 1β-merhylcarbapenem antibiotic of the general formula (XII). wherein R is the same as defined as above; Z is C3-C7 alkenyl, C1-20 alkyl, or methylene substituted with two groups selected from one group of aralkyl; Y is an oxygen atom, an sulfur atom, methylene or amine; and ring B is a benzene ring substituted with a halogen atom, a lower alkyl, or a lower alkoxy.
It has been reported that the second process is industrially more advantageous than the first process in terms of easier reaction steps and conditions.
Some similar process have been disclosed in a number of literatures (e.g., Tetrahedron pp. 2801, 1991: Tetrahedron Letters, 6625 pp, 1987: Japan Publication Patent Gazette Pyung 7-82248: same Gazette Pyung 7-82249).
β-methylcarbapenem antibiotic of the general formula (XII) may be made available through the well known process (e.g., Japan Publication Patent Pyung 4-279588) by reacting the general formula (V) compound with some heterocyclic thiol compound.
Nevertheless, the second process has recognized some disadvantage in terms of poor stereoselectivity.